Synergy Activity Of Tigecycline With Commonly Used Antimicrobials Against Carbapenem-Resistant Gram-negative Bacteria

Objective:To investigate the effects of tigecycline in combination with commonly used antimicrobials against Carbapenem-Resistant Enterobacteriaceae (CRE) and Carbapenmem-Resistant Acitobacter baumannii (CRAB).Methods:VITEK mass spectrometer was used for identification of isolates. Antimicrobial susceptibility testing was performed by agar dilution method. EDTA disk synergy test and modified Hodge test were used for detection of resistance phenotype. Resistance determinants were identified by PCR amplification and DNA sequence analysis. Multilocus sequence typing (MLST) was conducted for molecular typing of isolates to further reveal the molecular background of resistant strains. The effects of tigecycline in combination with 9 commonly used antimicrobials (including imipenem, meropenem, amoxicillin-clavulanic acid, piperacillin-tazobactam, levofloxacin, cefoperazone-sulbactam, moxifloxacin, amikacin and ceftazidime) against 29 CRE and 10 CRAB isolates were performed by chessboard dilution method.Results:Twenty-nine CRE isolates and 10 CRAB isolates were correctly identified to species by VITEK MS mass spectrometer. All of the 39 isolates were resistant to carbapenem and tigecycline. All of the isolates were positive for modified Hodge test, of which,29 were positive for EDTA disk synergy test. They were further confirmed to carry with blaNDM-1 by PCR amplification and DNA sequencing. Molecular typing indicated that a portion of the isolates studied were of high homology. ST114 was most prevalent among Enterobacter cloacae isolates, and ST167 was popular amongst Escherichia coli isolates. As for chessboard antimicrobial susceptibility testing, synergy and partial synergy effect were observed for tigecycline in combination with piperacillin-tazobactam (10.3% and 79.5%), levofloxacin (10.3% and 44.8%), moxifloxacin (13.8% and 72.4%), cefoperazone-sulbactam (7.1% and 75.0%), amikacin (3.4% and 31.0%) and ceftazidime (13.8% and 55.2%) against CRE isolates. While partial synergy effect was demonstrated for tigecycline in combination with imipenem (62.1%), meropenem (51.7%) and amoxicillin-clavulanic acid (10.4%) against CRE isolates. Amongst CRAB isolates, tigecycline in combination with imipenem (10.0% and 70.0%), meropenem (10.0% and 80.0%), amoxicillin-clavulanic acid (10.0% and 70.0%), levofloxacin (20.0% and 20.0%) and ceftazidime (40.0% and 50.0%) showed synergy and partial synergy effect. Partial synergy effect was observed for tigecycline in combination with piperacillin-tazobactam (100.0%), amikacin (90.0%), moxifloxacin (60.0%) and cefoperazone-sulbactam (30.0%) against CRAB isolates.Conclusion:The current study indicated that the most effective combinations against CRE and CRAB strains were the combinations of tigecycline with moxifloxacin and ceftazidime respectively. The results demonstrated that combined treatment of tigecycline with other antibiotics is more effective than active mono-therapy. The findings from this study indicate that there is a great potential of antibiotic combinations against carbapen-em-resistant Gram-negative pathogens, opening the way to a more rationale clinical assessment of novel combination therapies to combat infections caused by CRE and CRAB.